Concurrent Denosumab and Parenteral Iron Therapy Precipitating Severe Hypocalcemia and Hypophosphatemia

Abstract Denosumab-induced hypocalcemia and iron infusion–related hypophosphatemia are both well described. We describe a case of severe hypocalcemia and hypophosphatemia following sequential denosumab and parenteral iron administration. This resulted in respiratory failure due to muscle weakness and cardiac arrhythmia, requiring noninvasive ventilation and urgent intravenous electrolyte replacement. This case highlights the severe dysregulation in calcium and phosphate homeostasis that can occur with denosumab and iron infusions when administered in quick succession. Given that these drugs are among the most common therapies prescribed across a range of specialties, we hope to alert clinicians to this potential serious drug-drug interaction and suggest strategies for monitoring and management of the electrolyte derangement.


Introduction
Parenteral iron and denosumab are commonly prescribed in inpatient and community settings.Denosumab use has rapidly increased since its approval in 2010, and it is one of the most commonly prescribed osteoporosis therapies [1,2].Although fracture efficacy is well established, denosumab cessation has been associated with rebound bone loss and fractures [1], and denosumab-induced hypocalcemia can occur, particularly in advanced chronic kidney disease and vitamin D deficiency [3].With increasing indications, parenteral iron is also increasingly prescribed by a range of clinicians, including primary care, gastroenterology, nephrology, hematology, and internal medicine physicians [4].Parenteral iron impairs inactivation of fibroblast growth factor 23 (FGF23), leading to phosphaturia and reduced circulating 1,25-(OH)2 vitamin D, in turn reducing gastrointestinal phosphate absorption [5,6].FGF23-mediated hypophosphatemia occurs as a complication in up 45% to 47% of iron infusions, highest in those receiving ferric carboxymaltose (FCM) [7,8].
Severe hypocalcemia and hypophosphatemia caused by iron infusion and denosumab administered in close proximity has been reported [9][10][11][12][13].Raising awareness of this potential interaction is critical to avoid life-threatening electrolyte derangement.

Case Presentation
A 76-year-old man presented to the Emergency Department with lethargy, chest discomfort, and respiratory distress.Osteoporosis, based on a dual-energy x-ray absorptiometry (DXA)-derived bone density T-score at the hip and spine of −2.5 and −1.7 respectively, had been diagnosed by his primary care physician, who prescribed denosumab.There were no previous fractures.Kidney function, calcium, phosphate, and vitamin D levels had been normal.The first denosumab injection resulted in no known complications.There was also a history of iron deficiency anemia secondary to gastrointestinal angioectasias requiring 3 monthly iron infusions for the last year.Four weeks prior to presentation, the patient had received a second dose of subcutaneous denosumab 60 mg, and within 2 weeks was also administered intravenous iron polymaltose (IPM) (Fig. 1).He was also a heavy smoker with chronic obstructive airways disease, ischemic heart disease, cardiac failure, type 2 diabetes mellitus, hypertension, and a toxic multinodular goiter treated with antithyroid medications.
Respiratory support with noninvasive ventilation and urgent intravenous calcium gluconate and phosphate were administered.His respiratory acidosis resolved and QTc returned to the patient's baseline of 470 ms.Oral calcitriol, calcium carbonate, and phosphate supplementation were also commenced, and gradually weaned following discharge.Calcitriol was required for 4 weeks, and oral calcium and phosphate, with intermittently higher doses, were required for up to 12 months (Fig. 1).

Diagnostic Assessment
Two further iron infusions with IPM and FCM within 3 months were required despite multiple argon plasma coagulation treatments of angioectatic lesions (Fig. 1).Each subsequent iron infusion resulted in transient hypophosphatemia, but without hypocalcemia.A nadir serum phosphate of 0.43 mmol/L (1.33 mg/dL) was documented after FCM.Phosphate levels normalized with oral phosphate and calcitriol.
The patient was referred to the Metabolic Bone Disorder Clinic for investigation.Four weeks following FCM, the fractional excretion of phosphate was elevated at 36% (10%-20%).FGF23 levels were not available at the time of hypophosphatemia but were subsequently normal 10 weeks after his last FCM.Serum 1,25-(OH)2 vitamin D measured after calcitriol commencement was 106 pmol/L (44.2 pg/mL) (RR: 50-190 pmol/L, 20.8-79.2pg/mL).A secondary osteoporosis screen was negative.

Treatment
A presumptive diagnosis of recurrent iron infusion-related, FGF23-mediated hypophosphatemia was made, with a serious denosumab and iron infusion interaction causing severe hypocalcemia and hypophosphatemia.Denosumab was ceased due to concern for iron infusion-related osteomalacia and risk of electrolyte disturbance, given the likely need for further iron infusions.This was considered to outweigh the risk of rebound bone loss and fractures following denosumab cessation, particularly in the context of short duration of denosumab therapy.Recommendations were made to consider alternative preparations of iron and avoid future administration of IPM and FCM.
Subsequent parenteral iron therapy was changed to iron sucrose, which has since been administered on multiple occasions with close monitoring, with no further hypophosphatemia and normal FGF23 levels.
A repeat DXA at 24 months has shown stable hip and spine bone density and there were no new vertebral fractures on Vertebral Fracture Analysis.The patient has not sustained any clinical fractures in 2.5 years of follow-up.

Discussion
We present a case of severe symptomatic hypocalcemia and hypophosphatemia after co-administration of intravenous iron and denosumab, highlighting the dysregulation in calcium and phosphate homeostasis that can occur even in the setting of normal renal function and vitamin D levels.Given that these drugs are commonly prescribed across a range of specialties, and acute hypophosphatemia and hypocalcemia can cause tetany, cardiorespiratory failure, seizures, and coma in severe cases [5,7,8], clinicians need to be alert to this potential serious drug-drug interaction.Since 2016, there have been 6 published cases of electrolyte derangement following co-administration of denosumab and parenteral iron [9][10][11][12][13] (Table 1).Previously described cases were frequently asymptomatic and occurred in patients with varying renal function and 25-OH vitamin D levels.The present case was symptomatic and had complications of respiratory failure, QTc prolongation, and arrythmia, which resolved with urgent electrolyte replacement.In previously published cases [9][10][11][12][13], electrolyte disturbance occurred at 8 to 28 days after denosumab and 8 days to 2 months after intravenous iron.Iron and denosumab were given on the same day to 16 days apart, with the exception of one patient on years of recurrent iron infusions where the drugs were 2 months apart [10].Our patient similarly presented 4 weeks after denosumab and 2 weeks after IPM.It is likely that the risk is highest in the first month following denosumab administration.
The electrolyte disturbance which has been observed in patients receiving intravenous iron and denosumab is due to alterations in PTH, 1,25-(OH)2 vitamin D, and FGF23 (Fig. 2).Denosumab inhibits osteoclastic bone resorption, transiently reducing plasma calcium concentration, and resulting in elevated PTH levels [5].This secondary hyperparathyroidism decreases renal phosphate reabsorption, promoting phosphaturia.Iron infusions inhibit cleavage and inactivation of FGF23 [6].High levels of FGF23 decrease renal phosphate reabsorption and inhibit renal 1α-hydroxylation of 25-OH vitamin D to activated 1,25-(OH)2 vitamin D, thereby impairing intestinal absorption of calcium and phosphate [5].Since FGF23 impairs 1,25-(OH)2 vitamin D production, the compensatory response to hypocalcemia induced by denosumab is blunted in patients also receiving an iron infusion.Hence coadministration of iron infusions and denosumab are expected to amplify both the hypocalcemia and hypophosphatemia.
We would have expected our patient to have elevated FGF23, low 1,25-(OH)2 vitamin D, and high fractional excretion of phosphate during his time of hypophosphatemia and hypocalcemia, but they were not measured at that time.Normal FGF23 levels 10 weeks after intravenous FCM were found, at a time of normal serum phosphate.His 1,25-(OH) 2 vitamin D levels were also only checked after oral calcitriol.Hypophosphatemia and elevated FGF23 were not observed after changing to iron sucrose.This may be due to the waning effect of denosumab on PTH, or it may support the proposal that different iron preparations have varying risk of hypophosphatemia [7,8].Meta-analyses of randomized controlled trials, FCM was associated with an almost 8-fold and 9-fold higher risk of hypophosphatemia compared with ferric derisomaltose (FDI) and iron sucrose, respectively [8].Therefore, in patients requiring ongoing iron infusions, consideration should be given to trialing formulations less likely to cause hypophosphatemia.
We were concerned about osteomalacia in our patient, given that recurrent iron infusion-related hypophosphatemia has been associated with osteomalacia and increased fracture risk [7,8,14].In a similar case described by Fang et al [10], a 73-year-old woman who had received 2 years of recurrent iron infusions presented with bone pain, hypophosphatemia 0.27 mmol/L (0.84 mg/dL), and hypocalcemia 2.04 mmol/L (8.18 mg/dL) following her first dose of denosumab, and she was subsequently found to have osteomalacia-related fractures.In our patient, denosumab was ceased as a precaution.No transition to bisphosphonate therapy was planned, as it is contraindicated in iron infusion-related osteomalacia [14], and risk of rebound bone loss was thought to be lower following 2 doses of denosumab.Reassuringly, no evidence of increased bone turnover, loss of bone density, or clinical fractures have been observed over 2.5 years of follow-up.
Currently, there is lack of guidance on managing patients on denosumab therapy who also require iron infusions.This poses a management dilemma as long-term denosumab users cannot have their therapy delayed due to the risk of rebound bone loss and fractures.We recommend close monitoring of serum calcium and phosphate at 7, 14, and 28 days if coadministration cannot be avoided (Fig. 3).Based on our case and that of previously described cases [9][10][11][12][13], the highest risk period appears to be in the first month following denosumab administration, and cautious deferral of denosumab therapy for < 4 weeks could be considered.Evidence of hypocalcemia or hypophosphatemia should be promptly treated with calcitriol (given FGF23-mediated impairment of 1,25-(OH)2 vitamin D activation), as well as oral and/or intravenous calcium and phosphate replacement.Prophylactic replacement may be needed if ongoing intravenous iron and denosumab therapy is required.As hypomagnesemia can impair PTH secretion and activation of PTH receptors [15], correction of hypomagnesemia is also important.Given the lower reported risk with iron sucrose and FDI, use of these agents over FCM and IPM could be considered in those treated with denosumab, although further research is required to confirm in this population.
In summary, this case highlights that co-administration of iron infusions and denosumab may lead to severe lifethreatening electrolyte derangement and awareness of the interaction will hopefully lead to strategies to monitor and mitigate the electrolyte abnormalities.Further prospective studies are required to determine the frequency of this serious but likely underdiagnosed drug-drug interaction, the timing of electrolyte disturbance in order to refine monitoring strategies, and whether different iron preparations reliably reduce the risk of hypophosphatemia.

Learning Points
• Although denosumab-induced hypocalcemia and iron infusion-related hypophosphatemia are well described, coadministration of these agents may lead to severe lifethreatening electrolyte derangement requiring hospital admission and intravenous replacement.• Awareness of a drug interaction between denosumab and iron infusions should lead to strategies to monitor and mitigate the electrolyte abnormalities, that is, avoiding co-administration without delaying denosumab > 4 weeks, using alternative intravenous iron preparations associate with lower risk, and close monitoring of serum calcium and phosphate up to 1 month after administration.• Further research is necessary to determine the frequency and timing of this drug interaction, and to assess whether the use of alternative iron preparations may reliably reduce risk of developing an interaction.

Figure 3 .
Figure 3. Reducing risk hypocalcemia and hypophosphatemia: considerations in patients requiring intravenous iron and denosumab.Created with BioRender.com

Table 1 . Summary of findings from previously published cases of hypophosphatemia and hypocalcemia with iron infusions and denosumab Author, year Patient background (age, sex, clinical details) IV iron type, dose, timing a Denosumab dose, timing a Symptoms, electrolyte nadir Management and recovery
a Prior to presentation or first electrolyte disturbance noted.